Cathepsins are a family of enzymes included in the papain superfamily of cysteine proteases. Cathepsins B, C, F, H, K, L, S, V, and X have been described in the scientific literature. Cathepsin C is also known in the literature as Dipeptidyl Peptidase I or “DPPI.”
A number of recently published studies have begun to describe the role cathepsin C plays in certain inflammatory processes. See e.g. Adkison et al., The Journal of Clinical Investigation 109:363-371 (2002); Tran et al., Archives of Biochemistry and Biophysics 403:160-170 (2002); Thiele et al., The Journal of Immunology 158: 5200-5210 (1997); Bidere et al., The Journal of Biological Chemistry 277: 32339-32347 (2002); Mabee et al., The Journal of Immunology 160: 5880-5885; McGuire et al., The Journal of Biological Chemistry, 268: 2458-2467; and Paris et al., FEBS Letters 369: 326-330 (1995). From these studies, it appears that cathepsin C is co-expressed in granules with certain serine proteases and functions to process the pro-forms of these proteases to active forms, which are then released from the granules of inflammatory cells recruited to sites of inflammation. Once activated, these proteases have a number of functions including degradation of various extracellular matrix components, which together can propagate tissue damage and chronic inflammation.
For example, Chronic Obstructive Pulmonary Disease (“COPD”) is a chronic inflammatory disease where cathepsin C appears to play a role. Chronic bronchitis and emphysema usually occur together in COPD patients. Chronic bronchitis is generally characterized by a chronic productive cough, whereas emphysema is generally characterized by permanent enlargement of the airspaces distal to the terminal bronchioles and airway wall destruction.
Cigarette smoking is a significant risk factor for developing COPD. Exposure to cigarette smoke and other noxious particles and gases may result in chronic inflammation of the lung. In response to such exposure, inflammatory cells such as CD8+ T cells, macrophages, and neutrophils are recruited to the area. These recruited inflammatory cells release proteases, which are believed to play a major role in the disease etiology by a number of mechanisms. Proteases believed to be involved in this process include the serine proteases neutrophil elastase (“NE”), cathepsin G, and proteinase 3, all released from neutrophils; granzymes A and B, released from cytotoxic T cells or natural killer cells; and chymases, released from mast cells. Cathepsin C appears to be involved in activating all of these enzymes. Additionally, cathepsin C knockout mice are resistant to lung airspace enlargement and inflammatory cell infiltration in both cigarette smoke and ozone exposure models of COPD. See Guay et al., Current Topics in Medicinal Chemistry, 2010, 10, 708-716; See also Podolin et al. (2008), Inflammation Research, 57(Suppl 2) S104.
Rheumatoid arthritis (“RA”) is another chronic inflammatory disease where cathepsin C may play a role. Neutrophils are recruited to the site of joint inflammation and release cathepsin G, NE, and proteinase 3, which are believed to be responsible in part for cartilage destruction associated with RA (Hu, Y. and Pham, C. T. (2005) Arthritis Rheum 52: 2553-2558).
Other conditions where cathepsin C may play a role include osteoarthritis, asthma, and Multiple Sclerosis. See e.g. Matsui, K.; Yuyama, N.; Akaiwa, M.; Yoshida, N. L.; Maeda, M.; Sugita, Y.; Izuhara, K., Identification of an alternative splicing variant of cathepsin C/dipeptidyl-peptidase I, Gene. 293(1-2):1-7, 2002 Jun. 26; Wolters, P. J.; Laig-Webster, M.; Caughey, G. H., Dipeptidyl peptidase I cleaves matrix-associated proteins and is expressed mainly by mast cells in normal dog airways, American Journal of Respiratory Cell & Molecular Biology. 22(2):183-90, 2000.
One approach to treating these conditions is to inhibit the activity of the serine proteases involved in the inflammatory process, especially NE activity. See e.g., Ohbayashi, “Neutrophil elastase inhibitors as treatment for COPD”, Expert Opin. Investig. Drugs 11(7): 965-980 (2002); Shapiro, “Neutrophil Elastase: Path Clearer, Pathogen Killer, or Just Pathologic?”, Am. J. Respir. Cell Mol. Biol. 26: 266-268 (2002). In light of the role cathepsin C plays in activating certain serine proteases, especially NE, it is desirable to prepare compounds that inhibit its activity, which thereby inhibit serine protease activity. Thus, there is a need to identify compounds that inhibit cathepsin C, which can be used in the treatment of a variety of conditions mediated by cathepsin C.
There are additional activities of cathepsin C that may also be related to disease etiology. Cathepsin C has been demonstrated to have a role in neutrophil migration in the development of aortic aneurysms by a mechanism which has not been clearly elucidated (Pagano, M. B. et al. (2007) PNAS 104: 2855-2860). Thus, disease processes that involve neutrophil migration, as well as proteolytic enzyme release can be modulated by cathepsin C inhibition. Also, cathepsin C is highly expressed in the lung epithelium where it may play a role in the processing of other enzymes not yet identified. Cathepsin C has also been reported to cleave kallikrein-4, which is believed to play a role in dental enamel maturation (Tye, C. E. et al. (2009) J. Dental Res. 88: 323-327). Finally, cathepsin C is itself released from cells and may play a direct role in the degradation of matrix proteins.